Late onset of familial haemophagocytic lymphohistiocytosis 2 associated with heterozygous PRF1 mutation: challenges in diagnosis and treatment
DOI:
https://doi.org/10.15574/SP.2024.5(141).104112Keywords:
family hemophagocytic lymphohistiocytosis 2, pathological examination of bone marrow, PRF1 heterozygous mutation, whole exome sequencingAbstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition caused by immune overactivation. Familial HLH (f-HLH), such as f-HLH 2, is associated with mutations in the PRF1 gene, essential for ruling out secondary HLH.
Aim - to describe a clinical case of late onset f-HLH 2 associated with a heterozygous mutation in the PRF1 gene in a 13-year-old boy.
Case report. A 13-year-old boy presented with fever, nausea, vomiting, abdominal pain, and jaundice. Examination revealed hepatosplenomegaly, elevated liver enzymes, hyperbilirubinemia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and reduced NK-cells and T-lymphocytes. Cytomegalovirus (CMV) was detected by polymerase chain reaction. Pancytopenia soon developed. Bone marrow biopsy confirmed hemophagocytosis, leading to a diagnosis of secondary HLH associated with CMV. Treatment included intravenous immunoglobulin, HLH 2004 protocol (without etoposide), and ganciclovir, with initial improvement. However, cytopenia recurred after dexamethasone was stopped. Ruxolitinib was introduced alongside cyclosporine (CsA), leading to normalisation of liver function, spleen size, lymphocyte subpopulations, and haemogram. Cytopenia returned after ruxolitinib cessation. Whole-exome sequencing revealed a heterozygous PRF1 gene mutation, confirming the diagnosis of f-HLH 2.
Conclusions. Timely laboratory diagnostics, bone marrow biopsy, genetic testing, and appropriate treatment are critical in preventing complications and improving outcomes in HLH. Early intervention with specific therapies, such as immunosuppressants and genetic evaluation, is essential in managing f-HLH 2.
The study was conducted in accordance with the principles of the Declaration of Helsinki. The informed consent of the child's parents was obtained for the study.
The authors declare no conflict of interest.
References
Agbariah N, Sanz J, Rovó A. (2022). "A Dangerous Black Box:" Idiopathic Hemophagocytic Lymphohistiocytosis in Adult Patients-A Case Report and Review of the Literature. Case Rep Hematol. 2022: 5867129. https://doi.org/10.1155/2022/5867129
Albeituni S. (2024). Editorial: Towards a better understanding of hemophagocytic lymphohistiocytosis. Front Immunol. 15: 1385487. https://doi.org/10.3389/fimmu.2024.1385487
Bergsten E, Horne A, Aricó M, Astigarraga I, Egeler RM, Filipovich AH et al. (2017). Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 130(25): 2728-2738. Epub 2017 Sep 21. https://doi.org/10.1182/blood-2017-06-788349
Bergsten E, Horne A, Hed Myrberg I, Aricó M, Astigarraga I, Ishii E et al. (2020). Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study. Blood Adv. 4(15): 3754-3766. https://doi.org/10.1182/bloodadvances.2020002101
Bracaglia C, Sieni E, Cetica V, Da Ros M, Insalaco A, De Fusco C, et al. (2013). PReS-FINAL-2186: monoallelic mutations of familial hlh-related genes associated to macrophage activation syndrome. Pediatr Rheumatol Online J. 11; Suppl 2: O21. https://doi.org/10.1186/1546-0096-11-S2-O21
Canna SW, Marsh RA. (2020). Pediatric hemophagocytic lymphohistiocytosis. Blood. 135(16): 1332-1343. https://doi.org/10.1182/blood.2019000936
Cetica V, Sieni E, Pende D, Danesino C, De Fusco C, Locatelli F et al. (2016). Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry. J Allergy Clin Immunol. 137(1): 188-196.e4. Epub 2015 Sep 2. https://doi.org/10.1016/j.jaci.2015.06.048
Chi Y, Liu R, Zhou ZX, Shi XD, Ding YC, Li JG. (2021). Ruxolitinib treatment permits lower cumulative glucocorticoid dosing in children with secondary hemophagocytic lymphohistiocytosis. Pediatr Rheumatol Online J. 19(1): 49. https://doi.org/10.1186/s12969-021-00534-0
Chinn IK, Eckstein OS, Peckham-Gregory EC, Goldberg BR, Forbes LR, Nicholas SK et al. (2018). Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis. Blood. 132(1): 89-100. Epub 2018 Apr 9. https://doi.org/10.1182/blood-2017-11-814244
Chinnici A, Beneforti L, Pegoraro F, Trambusti I, Tondo A, Favre C et al. (2023). Approaching hemophagocytic lymphohistiocytosis. Front Immunol. 14: 1210041. https://doi.org/10.3389/fimmu.2023.1210041
Ciambotti B, Mussolin L, d'Amore ES, Pillon M, Sieni E, Coniglio ML et al. (2014). Monoallelic mutations of the perforin gene may represent a predisposing factor to childhood anaplastic large cell lymphoma. J Pediatr Hematol Oncol. 36(6): e359-365. https://doi.org/10.1097/MPH.0000000000000073
De Armas R, Sindou P, Gelot A, Routon MC, Ponsot G, Vallat JM. (2004). Demyelinating peripheral neuropathy associated with hemophagocytic lymphohistiocytosis. An immuno-electron microscopic study. Acta Neuropathol. 108(4): 341-344. Epub 2004 Jul 9. https://doi.org/10.1007/s00401-004-0897-0
Dong Y, Wang T, Wu H. (2024). Heterogeneity of macrophage activation syndrome and treatment progression. Front Immunol. 15: 1389710. https://doi.org/10.3389/fimmu.2024.1389710
Eichenauer DA, Böll B. (2023). Diagnostics and treatment of hemophagocytic lymphohistiocytosis. Inn Med (Heidelb). 64(11): 1077-1084. Epub 2023 Oct 19. https://doi.org/10.1007/s00108-023-01596-w
Fitzgerald NE, MacClain KL. (2003). Imaging characteristics of hemophagocytic lymphohistiocytosis. Pediatr Radiol. 33(6): 392-401. Epub 2003 Mar 21. https://doi.org/10.1007/s00247-003-0894-9
Gars E, Purington N, Scott G, Chisholm K, Gratzinger D, Martin BA, Ohgami RS. (2018). Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica. 103(10): 1635-1641. Epub 2018 Jun 14. https://doi.org/10.3324/haematol.2017.186627
Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S et al. (2007). HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 48(2): 124-131. https://doi.org/10.1002/pbc.21039
Hines MR, von Bahr Greenwood T, Beutel G, Beutel K, Hays JA et al. (2022). Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults. Crit Care Med. 50(5): 860-872. Epub 2021 Oct 5. PMID: 34605776. https://doi.org/10.1097/CCM.0000000000005361
Hoshino A, Xi Y, Nakao T, Kato K, Fujiyama S, Koh K et al. (2020). A Cry for the Development of Newborn Screening for Familial Hemophagocytic Lymphohistiocytosis. J Clin Immunol. 40(8): 1196-1198. Epub 2020 Sep 10. https://doi.org/10.1007/s10875-020-00863-x
Isaacs H Jr. (2006). Fetal and neonatal histiocytoses. Pediatr Blood Cancer. 47(2): 123-129. https://doi.org/10.1002/pbc.20725
Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. (2011). How I treat hemophagocytic lymphohistiocytosis. Blood. 118(15): 4041-4052. Epub 2011 Aug 9. https://doi.org/10.1182/blood-2011-03-278127
Kaçar AG, Celkan TT. (2022). Hemophagocytic Lymphohistiocytosis. Balkan Med J. 39(5): 309-317. Epub 2022 Aug 15. https://doi.org/10.4274/balkanmedj.galenos.2022.2022-4-83
Keenan C, Nichols KE, Albeituni S. (2021). Use of the JAK Inhibitor Ruxolitinib in the Treatment of Hemophagocytic Lymphohistiocytosis. Front Immunol. 12: 614704. https://doi.org/10.3389/fimmu.2021.614704
Lafarge A, Chean D, Whiting L, Clere-Jehl R et al. (2024). Management of hematological patients requiring emergency chemotherapy in the intensive care unit. Intensive Care Med. Epub ahead of print. https://doi.org/10.1007/s00134-024-07454-z
Liu P, Pan X, Chen C, Niu T, Shuai X, Wang J et al. (2020). Nivolumab treatment of relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults. Blood. 135(11): 826-833. https://doi.org/10.1182/blood.2019003886
Ma H, Zhang R, Zhang L, Wei A, Zhao X, Yang Y et al. (2020). Treatment of pediatric primary hemophagocytic lymphohistiocytosis with the HLH-94/2004 regimens and hematopoietic stem cell transplantation in China. Ann Hematol. 99(10): 2255-2263. Epub 2020 Aug 6. https://doi.org/10.1007/s00277-020-04209-w
Morrell DS, Pepping MA, Scott JP, Esterly NB, Drolet BA. (2002). Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol. 138(9): 1208-1212. https://doi.org/10.1001/archderm.138.9.1208
Niece JA, Rogers ZR, Ahmad N, Langevin AM, McClain KL. (2010). Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer. 54(3): 424-428. https://doi.org/10.1002/pbc.22359
Niizato D, Isoda T, Mitsuiki N, Kaneko S, Tomomasa D, Kamiya T et al. (2022). Case report: Optimized ruxolitinib-based therapy in an infant with familial hemophagocytic lymphohistiocytosis type 3. Front Immunol. 13: 977463. https://doi.org/10.3389/fimmu.2022.977463
Palazzi DL, McClain KL, Kaplan SL. (2003). Hemophagocytic syndrome after Kawasaki disease. Pediatr Infect Dis J. 22(7): 663-666. https://doi.org/10.1097/01.inf.0000073061.55674.1b
Palazzi DL, McClain KL, Kaplan SL. (2003). Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis. 36(3): 306-312. Epub 2003 Jan 14. https://doi.org/10.1086/345903
Rivière S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O, Fardet L. (2014). Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med. 127(11): 1118-1125. Epub 2014 May 14. https://doi.org/10.1016/j.amjmed.2014.04.034
Sieni E, Cetica V, Piccin A, Gherlinzoni F, Sasso FC, Rabusin M et al. (2012). Familial hemophagocytic lymphohistiocytosis may present during adulthood: clinical and genetic features of a small series. PloS One. 7(9): e44649. https://doi.org/10.1371/journal.pone.0044649
Song Y, Li X, He X, Zhou F, Du F, Wang Z et al. (2023). Dose-escalating ruxolitinib for refractory hemophagocytic lymphohistiocytosis. Front Immunol. 14: 1211655. https://doi.org/10.3389/fimmu.2023.1211655
Song Y, Zhou F, Du F, Wang Z, Bai L, Yao Y et al. (2024). Combined emapalumab and ruxolitinib in patients with haemophagocytic Lymphohistiocytosis. Blood Cancer J. 14(1): 70. https://doi.org/10.1038/s41408-024-01056-0
Tang Z, Zhu D, Li X, Yan H, Luo T, Xie L et al. (2024). Development and validation of an early mortality risk model for pediatric hemophagocytic lymphohistiocytosis: a comparison with HScore, PELOD-2, P-MODS, and pSOFA. Ann Hematol. Epub ahead of print. https://doi.org/10.1007/s00277-024-05780-2
Triebwasser MP, Barrett DM, Bassiri H, Bunin N, Elgarten C, Freedman J et al. (2021). Combined use of emapalumab and ruxolitinib in a patient with refractory hemophagocytic lymphohistiocytosis was safe and effective. Pediatr Blood Cancer. 68(7): e29026. Epub 2021 Mar 22. https://doi.org/10.1002/pbc.29026
Vallurupalli M, Berliner N. (2019). Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis. Blood. 134(21): 1783-1786. https://doi.org/10.1182/blood.2019002289
Vignesh P, Loganathan SK, Sudhakar M, Chaudhary H, Rawat A, Sharma M et al. (2021). Hemophagocytic Lymphohistiocytosis in Children with Chronic Granulomatous Disease-Single-Center Experience from North India. J Allergy Clin Immunol Pract. 9(2): 771-782.e3. Epub 2020 Nov 28. https://doi.org/10.1016/j.jaip.2020.11.041
Whaley BF. (2011). Familial hemophagocytic lymphohistiocytosis in the neonate. Adv Neonatal Care. 11(2): 101-107. https://doi.org/10.1097/ANC.0b013e318210d02c
Xin X, Wang N, Zhang Y. (2023). Hemophagocytic lymphohistiocytosis with a hemizygous PRF1 c.674G>A mutation. Am J Med Sci. 366(5): 387-394. Epub 2023 Jul 17. https://doi.org/10.1016/j.amjms.2023.07.005
Yang Y, Luo Z, Yuan T. (2021). Familial hemophagocytic lymphohistiocytosis in a neonate: Case report and literature review. Medicine (Baltimore). 100(47): e27786. https://doi.org/10.1097/MD.0000000000027786
Zhang K, Astigarraga I, Bryceson Y, Lehmberg K, Machowicz R, Marsh R et al. (2006). Familial Hemophagocytic Lymphohistiocytosis. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.
Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J et al. (2011). Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 118(22): 5794-5798. Epub 2011 Aug 31. https://doi.org/10.1182/blood-2011-07-370148
Zhang Q, Zhao YZ, Ma HH, Wang D, Cui L, Li WJ et al. (2022). A study of ruxolitinib response-based stratified treatment for pediatric hemophagocytic lymphohistiocytosis. Blood. 139(24): 3493-3504. https://doi.org/10.1182/blood.2021014860
Downloads
Published
Issue
Section
License
Copyright (c) 2024 Modern pediatrics. Ukraine
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The policy of the Journal “MODERN PEDIATRICS. UKRAINE” is compatible with the vast majority of funders' of open access and self-archiving policies. The journal provides immediate open access route being convinced that everyone – not only scientists - can benefit from research results, and publishes articles exclusively under open access distribution, with a Creative Commons Attribution-Noncommercial 4.0 international license (СС BY-NC).
Authors transfer the copyright to the Journal “MODERN PEDIATRICS. UKRAINE” when the manuscript is accepted for publication. Authors declare that this manuscript has not been published nor is under simultaneous consideration for publication elsewhere. After publication, the articles become freely available on-line to the public.
Readers have the right to use, distribute, and reproduce articles in any medium, provided the articles and the journal are properly cited.
The use of published materials for commercial purposes is strongly prohibited.
